Amino acids

All peptides and polypeptides are polymers of α-amino acids. There are 20 α-amino acids that are relevant to the make-up of mammalian proteins (see below). Several other amino acids are found in the body free or in combined states (i.e. not associated with peptides or proteins). These non-protein associated amino acids perform specialized functions. Several of the amino acids found in proteins also serve functions distinct from the formation of peptides and proteins, e.g., tyrosine in the formation of thyroid hormones or glutamate acting as a neurotransmitter.

The α-amino acids in peptides and proteins (excluding proline) consist of a carboxylic acid (–COOH) and an amino (–NH₂) functional group attached to the same tetrahedral carbon atom. This carbon is the α-carbon. Distinct R-groups, that distinguish one amino acid from another, also are attached to the alpha-carbon (except in the case of glycine where the R-group is hydrogen). The fourth substitution on the tetrahedral α-carbon of amino acids is hydrogen.

Table of α-amino acids found in proteins

Amino acid	Symbol	Structure*	pK1 (COOH)	pK2 (NH2)	pK R Group
Amino acids with aliphatic R-groups
Glycine	Gly – G		2.4	9.8
Alanine	Ala – A		2.4	9.9
Valine	Val – V		2.2	9.7
Leucine	Leu – L		2.3	9.7
Isoleucine	Ile – I		2.3	9.8
Non-aromatic amino acids with hydroxyl R-groups
Serine	Ser – S		2.2	9.2	≈13
Threonine	Thr – T		2.1	9.1	≈13
Amino acids with sulfur-containing R-groups
Cysteine	Cys – C		1.9	10.8	8.3
Methionine	Met – M		2.1	9.3
Acidic amino acids and their amides
Aspartic Acid	Asp – D		2.0	9.9	3.9
Asparagine	Asn – N		2.1	8.8
Glutamic Acid	Glu – E		2.1	9.5	4.1
Glutamine	Gln – Q		2.2	9.1
Basic amino acids
Arginine	Arg – R		1.8	9.0	12.5
Lysine	Lys – K		2.2	9.2	10.8
Histidine	His – H		1.8	9.2	6.0
Amino acids with aromatic rings
Phenylalanine	Phe – F		2.2	9.2
Tyrosine	Tyr – Y		2.2	9.1	10.1
Tryptophan	Trp – W		2.4	9.4
Imino acids
Proline	Pro – P		2.0	10.6

^*Backbone of the amino acids is red, R-groups are black.

Carbohydrates

Carbohydrates are carbon compounds that contain large quantities of hydroxyl groups. All carbohydrates can be classified as either monosaccharides, oligosaccharides or polysaccharides. Anywhere from two to ten monosaccharide units, linked by glycosidic bonds, make up an oligosaccharide. Polysaccharides are much larger, containing hundreds of monosaccharide units. The presence of the hydroxyl groups allows carbohydrates to interact with the aqueous environment and to participate in hydrogen bonding, both within and between chains. Derivatives of the carbohydrates can contain nitrogens, phosphates and sulfur compounds. Carbohydrates also can combine with lipid to form glycolipids or with protein to form glycoproteins. Carbohydrates can exist in either of two conformations, as determined by the orientation of the hydroxyl group about the asymmetric carbon farthest from the carbonyl. With a few exceptions, those carbohydrates that are of physiological significance exist in the D-conformation. The mirror-image conformations, called enantiomers, are in the L-conformation.

Structures of glyceraldehyde enantiomers

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Monosaccharides

The monosaccharides commonly found in humans are classified according to the number of carbons they contain in their backbone structures. The major monosaccharides contain four to six carbon atoms. The spatial relationships of the atoms of the ring structures are more correctly described by the two conformations identified as the chair form and the boat form. The chair form is the more stable of the two.

α-D-Glucose            Chair form of α-D-Glucose

 

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Disaccharides

Covalent bonds between the hydroxyl of a cyclic sugar and the hydroxyl of a second sugar (or another alcohol containing compound) are termed glycosidic bonds, and the resultant molecules are glycosides. The linkage of two monosaccharides to form disaccharides involves a glycosidic bond. Several physiogically important disaccharides are sucrose, lactose and maltose.

Sucrose: prevalent in sugar cane and sugar beets, is composed of glucose and fructose through an α–(1,2)–β-glycosidic bond.

Sucrose

 

Lactose: is found exclusively in the milk of mammals and consists of galactose and glucose in a β–(1,4) glycosidic bond.

Lactose

 

Maltose: the major degradation product of starch, is composed of 2 glucose monomers in an α–(1,4) glycosidic bond.

Maltose

 

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Polysaccharides

Most of the carbohydrates found in nature occur in the form of high molecular weight polymers called polysaccharides. The monomeric building blocks used to generate polysaccharides can be varied; in all cases, however, the predominant monosaccharide found in polysaccharides is D-glucose. When polysaccharides are composed of a single monosaccharide building block, they are termed homopolysaccharides. Polysaccharides composed of more than one type of monosaccharide are termed heteropolysaccharides.

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Glycogen

Glycogen is the major form of stored carbohydrate in animals. This crucial molecule is a homopolymer of glucose in α–(1,4) linkage; it is also highly branched, with α–(1,6) branch linkages occurring every 8-10 residues. Glycogen is a very compact structure that results from the coiling of the polymer chains. This compactness allows large amounts of carbon energy to be stored in a small volume, with little effect on cellular osmolarity.

Section of glycogen showing α–1,4– and α–1,6–glycosidic linkages

 

Lipids

Biological molecules that are insoluble in aqueous solutions and soluble in organic solvents are classified as lipids. The biological lipids of physiological importance for humans have four major functions:

1. They serve as structural components of biological membranes.

2. They provide energy reserves, predominantly in the form of triacylglycerols.

3. Both lipids and lipid derivatives serve as vitamins and hormones.

4. Lipophilic bile acids aid in lipid solubilization.

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Fatty acids

Fatty acids fill two major roles in the body:

1. as the components of more complex membrane lipids.

2. as the major components of stored fat in the form of triacylglycerols.

Fatty acids are long-chain hydrocarbon molecules containing a carboxylic acid moiety at one end. The numbering of carbons in fatty acids begins with the carbon of the carboxylate group. At physiological pH, the carboxyl group is readily ionized, rendering a negative charge onto fatty acids in bodily fluids.

Fatty acids that contain no carbon-carbon double bonds are termed saturated fatty acids; those that contain double bonds are unsaturated fatty acids and fatty acids with multiple sites of unsaturation are termed polyunsaturated fatty acids (PUFAs). The numeric designations used for fatty acids come from the number of carbon atoms, followed by the number of sites of unsaturation (eg, palmitic acid is a 16-carbon fatty acid with no unsaturation and is designated by 16:0).

Palmitic acid

The site of unsaturation in a fatty acid is indicated by the symbol Δ and the number of the first carbon of the double bond relative to the carboxylic acid group (–COOH) carbon which is designated carbon #1. For example, palmitoleic acid is a 16-carbon fatty acid with one site of unsaturation between carbons 9 and 10, and is designated by 16:1^Δ9. Saturated fatty acids of less than eight carbon atoms are liquid at physiological temperature, whereas those containing more than ten are solid. The presence of double bonds in fatty acids significantly lowers the melting point relative to a saturated fatty acid. The majority of fatty acids found in the body are acquired in the diet. However, the lipid biosynthetic capacity of the body (fatty acid synthase and other fatty acid modifying enzymes) can supply the body with all the various fatty acid structures needed. Two key exceptions to this are the PUFAs known as linoleic acid and α-linolenic acid, containing unsaturation sites beyond carbons 9 and 10 (relative to the α-COOH group). These two fatty acids cannot be synthesized from precursors in the body, and are thus considered the essential fatty acids; essential in the sense that they must be provided in the diet. Since plants are capable of synthesizing linoleic and α-linolenic acid, humans can acquire these fats by consuming a variety of plants or else by eating the meat of animals that have consumed these plant fats. These two essential fatty acids are also referred to as omega fatty acids. The use of the greek omega, ω, refers to the end of the fatty acid opposite to that of the –COOH group. Linoleic acid is an omega-6 PUFA and α-linolenic is an omega-3 PUFA (see Table below).

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Physiologically relevant fatty acids

Numerical symbol	Common name and structure	Comments
14:0	Myristic acid	Often found attached to the N-term. of plasma membrane-associated cytoplasmic proteins
16:0	Palmitic acid	End product of mammalian fatty acid synthesis
16:1Δ9	Palmitoleic acid
18:0	Stearic acid
18:1Δ9	Oleic acid	An omega-9 monounsaturated fatty acid
18:2Δ9,12	Linoleic acid	Essential fatty acid An omega-6 polyunsaturated fatty acid
18:3Δ9,12,15	α-Linolenic acid (ALA)	Essential fatty acid An omega-3 polyunsaturated fatty acid
20:4Δ5,8,11,14	Arachidonic acid	An omega-6 polyunsaturated fatty acid Precursor for eicosanoid synthesis
20:5Δ5,8,11,14,17	Eicosapentaenoic acid (EPA)	An omega-3 polyunsaturated fatty acid enriched in fish oils
22:6Δ4,7,10,13,16,19	Docosahexaenoic acid (DHA)	An omega-3 polyunsaturated fatty acid enriched in fish oils

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Basic structure of phospholipids

The basic structure of phospolipids is very similar to that of the triacylglycerides. The building block of the phospholipids is phosphatidic acid which results when the X substitution in the basic structure shown in the Figure below is a hydrogen atom. Substitutions include ethanolamine (phosphatidylethanolamine), choline (phosphatidylcholine, also called lecithins), serine (phosphatidylserine), glycerol (phosphatidylglycerol), myo-inositol (phosphatidylinositol, these compounds can have a variety in the numbers of inositol alcohols that are phosphorylated generating polyphosphatidylinositols), and phosphatidylglycerol (diphosphatidylglycerol more commonly known as cardiolipins).

Basic composition of a phospholipid. X can be a number of different substituents.

 

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Basic structure of sphingolipids

Sphingolipids are composed of a backbone of sphingosine which is derived itself from glycerol. Sphingosine is N-acetylated by a variety of fatty acids generating a family of molecules referred to as ceramides. Sphingolipids predominate in the myelin sheath of nerve fibers. Sphingomyelin is an abundant sphingolipid generated by transfer of the phosphocholine moiety of phosphatidylcholine to a ceramide, thus sphingomyelin is a unique form of a phospholipid. The other major class of sphingolipids (besides the sphingomyelins) are the glycosphingolipids generated by substitution of carbohydrates to the sn1 carbon of the glycerol backbone of a ceramide. There are 4 major classes of glycosphingolipids:

Cerebrosides: contain a single moiety, principally galactose.

Sulfatides: sulfuric acid esters of galactocerebrosides.

Globosides: contain 2 or more sugars.

Gangliosides: similar to globosides except also contain sialic acid.

Sphingosine

Basic composition of a ceramide

"n" indicates any fatty acid may be N-acetylated at this position.

 

 

Nucleic acids

As a class, the nucleotides may be considered one of the most important metabolites of the cell. Nucleotides are found primarily as the monomeric units comprising the major nucleic acids of the cell, RNA and DNA. However, they also are required for numerous other important functions within the cell. These functions include:

1. serving as energy stores for future use in phosphate transfer reactions. These reactions are predominantly carried out by ATP.

2. forming a portion of several important coenzymes such as NAD⁺, NADP⁺, FAD and coenzyme A.

3. serving as mediators of numerous important cellular processes such as second messengers in signal transduction events. The predominant second messenger is cyclic-AMP (cAMP), a cyclic derivative of AMP formed from ATP.

4. controlling numerous enzymatic reactions through allosteric effects on enzyme activity.

5. serving as activated intermediates in numerous biosynthetic reactions. These activated intermediates include S-adenosylmethionine (S-AdoMet or SAM) involved in methyl transfer reactions as well as the many sugar coupled nucleotides involved in glycogen and glycoprotein synthesis.

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Nucleoside and nucleotide structure and nomenclature

The nucleotides found in cells are derivatives of the heterocyclic highly basic compounds purine and pyrimidine.

Purine	Pyrimidine

It is the chemical basicity of the nucleotides that has given them the common term "bases" as they are associated with nucleotides present in DNA and RNA. There are five major bases found in cells. The derivatives of purine are called adenine and guanine, and the derivatives of pyrimidine are called thymine, cytosine and uracil. The common abbreviations used for these five bases are, A, G, T, C and U.

Base Formula	Base (X=H)	Nucleoside X=ribose or deoxyribose	Nucleotide X=ribose phosphate
	Cytosine, C	Cytidine, C	Cytidine monophosphate, CMP
	Uracil, U	Uridine, U	Uridine monophosphate, UMP
	Thymine, T	Thymidine, T (only deoxyribose)	Thymidine monophosphate, TMP
	Adenine, A	Adenosine, A	Adenosine monophosphate, AMP
	Guanine, G	Guanosine, G	Guanosine monophosphate, GMP

The purine and pyrimidine bases in cells are linked to carbohydrate and in this form are termed, nucleosides. Nucleosides are found in the cell primarily in their phosphorylated form. These are termed nucleotides. The most common site of phosphorylation of nucleotides found in cells is the hydroxyl group attached to the 5'-carbon of the ribose The carbon atoms of the ribose present in nucleotides are designated with a prime (') mark to distinguish them from the backbone numbering in the bases. Nucleotides can exist in the mono-, di-, or tri-phosphorylated forms.

Nucleotides are given distinct abbreviations to allow easy identification of their structure and state of phosphorylation. The monophosphorylated form of adenosine (adenosine-5'-monophosphate) is written as, AMP. The di- and tri-phosphorylated forms are written as, ADP and ATP, respectively. The use of these abbreviations assumes that the nucleotide is in the 5'-phosphorylated form. The nucleotides found in DNA are unique from those of RNA in that the ribose exists in the 2'-deoxy form and the abbreviations of the nucleotides contain a "d" designation. The monophosphorylated form of adenosine found in DNA (deoxyadenosine-5'-monophosphate) is written as dAMP.

The nucleotide uridine is never found in DNA and thymine is almost exclusively found in DNA. Thymine is found in tRNAs but not rRNAs nor mRNAs. There are several less common bases found in DNA and RNA. The primary modified base in DNA is 5-methylcytosine. A variety of modified bases appear in the tRNAs. Many modified nucleotides are encountered outside of the context of DNA and RNA that serve important biological functions.

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Adenosine derivatives

The most common adenosine derivative is the cyclic form, 3'-5'-cyclic adenosine monophosphate, cAMP. This compound is a very powerful second messenger involved in passing signal transduction events from the cell surface to internal proteins, e.g. cAMP-dependent protein kinase, PKA. PKA phosphorylates a number of proteins, thereby, affecting their activity either positively or negatively. Cyclic-AMP is also involved in the regulation of ion channels by direct interaction with the channel proteins, e.g. in the activation of odorant receptors by odorant molecules. Formation of cAMP occurs in response to activation of receptor-coupled adenylate cyclase. These receptors can be of any type, e.g. hormone receptors or odorant receptors.

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Guanosine derivatives

A cyclic form of GMP (cGMP) also is found in cells involved as a second messenger molecule. In many cases its' role is to antagonize the effects of cAMP. Formation of cGMP occurs in response to receptor mediated signals similar to those for activation of adenylate cyclase. However, in this case it is guanylate cyclase that is coupled to the receptor. The most important cGMP coupled signal transduction cascade is that photoreception. However, in this case activation of rhodopsin (in the rods) or other opsins (in the cones) by the absorption of a photon of light (through 11-cis-retinal covalently associated with rhodopsin and opsins) activates transducin which in turn activates a cGMP specific phosphodiesterase that hydrolyzes cGMP to GMP. This lowers the effective concentration of cGMP bound to gated ion channels resulting in their closure and a concomitant hyperpolarization of the cell.

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Synthetic nucleotide analogs

Many nucleotide analogues are chemically synthesized and used for their therapeutic potential. The nucleotide analogues can be utilized to inhibit specific enzymatic activities. A large family of analogues are used as anti-tumor agents, for instance, because they interfere with the synthesis of DNA and thereby preferentially kill rapidly dividing cells such as tumor cells. Some of the nucleotide analogues commonly used in chemotherapy are 6-mercaptopurine, 5-fluorouracil, 5-iodo-2'-deoxyuridine and 6-thioguanine. Each of these compounds disrupts the normal replication process by interfering with the formation of correct Watson-Crick base-pairing. Nucleotide analogs also have been targeted for use as antiviral agents. Several analogs are used to interfere with the replication of HIV, such as AZT (azidothymidine) and ddI (dideoxyinosine). Several nucleotide analogues are used after organ transplantation in order to suppress the immune system and reduce the likelihood of transplant rejection by the host.

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Polynucleotides

Polynucleotides are formed by the condensation of two or more nucleotides. The condensation most commonly occurs between the alcohol of a 5'-phosphate of one nucleotide and the 3'-hydroxyl of a second, with the elimination of H₂O, forming a phosphodiester bond. The formation of phosphodiester bonds in DNA and RNA exhibits directionality. The primary structure of DNA and RNA (the linear arrangement of the nucleotides) proceeds in the 5'—>3' direction. The common representation of the primary structure of DNA or RNA molecules is to write the nucleotide sequences from left to right synonymous with the 5'—>3' direction: 5'-pGpApTpC-3'

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